Background

Flurizan™ is the R-enantiomer of the nonsteroidal anti-inflammatory flurbiprofen, an NSAID that is structurally and pharmacologically related to ibuprofen and is used to treat several inflammatory conditions. As a selective Aβ42-lowering agent (aka SALA), Flurizan™ would have been the first in its class to treat Alzheimer's disease. The rationale for testing Flurizan™ in Alzheimer's is that it can modulate γ-secretase, the enzyme complex that cleaves the Aβ peptide off its precursor protein, to selectively reduce generation of long, aggregation-prone forms of Aβ without affecting γ-secretase cleavage of other substrates, such as Notch.

Epidemiological research has shown that long-term use of NSAIDs is associated with a reduced risk for development of Alzheimer disease. In contrast to S-fluriprofen, the R-enantiomer is inactive toward the cyclooxygenase enzyme, and hence causes fewer gastrointestinal side effects. In cell-based and animal studies, Flurizan™ has been shown to lower Aβ42, probably through a direct effect on y-secretase (see Weggen et al., 2001;Weggen et al., 2003). The presenilin component of the y-secretase intramembrane complex is thought to be the target of Flurizan™'s activity (see Eriksen et al., 2003;Beher et al., 2004).

Findings

A 12-month Phase 2 study in 210 people with mild to moderate Alzheimer's disease compared 400–800 mg of Flurizan™ twice daily to placebo for effects on cognition and function. A 12-month extension was added to the placebo-controlled phase of the trial. This trial found no effect on cognition, but did report a small treatment benefit on function, only for the higher dose and only in mild AD. Side effects included nausea, dizziness, and diarrhea, but overall Flurizan™ was tolerated well (see Wilcock et al., 2008).

However, a Phase 1 trial of 400 to 1,600 mg/day of Flurizan™ in 48 healthy volunteers generated CSF pharmacodynamic data, suggesting low exposure of the drug in the brain. In particular, CSF Aβ42 did not change with 21 days of dosing (see Galasko et al., 2007).

A subsequent 18-month Phase 3 trial in 1,600 AD patients carried out at 133 centers in the United States initially compared twice-daily doses of 400 and 800 mg of Flurizan™ to placebo. After analysis of the Phase 2 trial data, the Phase 3 trial was modified, with the approval of the FDA, so that only the highest dose was administered and only to patients with mild AD; patients with moderate AD were dropped from the trial. There was no difference between the treatment and placebo arms in either the co-primary outcomes (the ADAS-Cog and the ADCS activities of daily living scales) or a range of secondary outcomes that included measures of function (the CDR sum-of-boxes), cognition (the MMSE), psychopathology (Neuropsychiatric Inventory), quality of life (QQL-AD), and caregiver burden (see Aug 2008 conference story; Green et al., 2009). The failure of Flurizan™ is generally attributed to its insufficient pharmacodynamics, i.e., inadequate ability to penetrate the brain and engage its target protein at doses sufficient to yield an effect. Two additional Phase 3 trials were terminated and further development of Flurizan™ was discontinued. Separate clinical development of Flurizan™ for prostate cancer has also been discontinued following negative Phase 2 results.